A Prospective, Exploratory Study of Becotatug Vedotin Plus Putlimab for Neoadjuvant Therapy and Adjuvant Radiotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma

Prior treatment

• Prior receipt of any form of anti-tumor therapy for the primary tumor or metastatic lymph nodes, including chemotherapy, radiotherapy, targeted therapy, anti-PD-1 or anti-PD-L1 therapy, or surgery (biopsy excluded);
• Concurrent participation in another clinical study;

Other illness

• History of Grade ≥3 immune-related adverse events or treatment-related adverse events that have not recovered to Grade ≤1;
• Receipt of surgery, chemotherapy, targeted small molecule therapy, or radiotherapy for another invasive malignancy within the past 5 years;
• Autoimmune disease requiring systemic corticosteroid therapy within the past 3 months, history of clinically significant autoimmune disease, or syndrome requiring systemic corticosteroid therapy;
• Active infection requiring systemic treatment;
• History of other malignancies;
• History of organ transplantation;
• History of autoimmune disease, or other conditions requiring long-term systemic corticosteroid or immunosuppressive therapy;
• Positive for human immunodeficiency virus (HIV);
• Active hepatitis B or hepatitis C infection (HBV DNA or HCV RNA above the upper limit of normal);
• Serious cardiovascular, respiratory, or major immune system comorbidities; including urinary tract obstruction, myocardial infarction, arrhythmia, obstructive or restrictive lung disease, or other conditions that the Investigator considers may increase subject risk;
• History of psychiatric disorders (e.g., schizophrenia, mania, anxiety disorder, depression, phobia, etc.) or subjects/spouses diagnosed with psychiatric illness at the time of study enrollment;
• Any other condition that the Investigator considers renders the subject unsuitable for enrollment or may interfere with subject participation or completion of the study.

Lab values

• Total white blood cell count \<3.5×10⁹/L, absolute lymphocyte count \<0.8×10⁹/L, neutrophil count \<1.5×10⁹/L, platelet count \<100×10⁹/L, or hemoglobin \<90 g/L; total bilirubin \>1.5× upper limit of normal (ULN), transaminases (AST, ALT) \>3× ULN (\>5× ULN if hepatic metastases present), serum creatinine \>1.5× ULN; coagulation abnormalities with international normalized ratio (INR) or prothrombin time (PT) \>1.5× ULN;

Other

• Presence of distant metastatic lesions;
• Pregnant or lactating women;
• Refusal to use effective contraception during the treatment period and for 3 months thereafter;
• Critically ill patients unable to complete the study assessments;
• Subjects or spouses with communication barriers or inability to provide normal responses due to altered consciousness, aphasia, intellectual disability, or other causes;

• Diagnosis of any malignancy other than gastric cancer within 5 years prior to the first dose, with the exception of adequately treated cutaneous basal cell carcinoma, cutaneous squamous cell carcinoma, and/or radically resected carcinoma in situ;
• Known endoscopic evidence of active bleeding in the target lesion;
• Concurrent participation in another interventional clinical study, or receipt of any investigational medicinal product or use of investigational device within 4 weeks prior to the first dose;
• Prior exposure to any of the following therapies: anti-PD-1, anti-PD-L1, or anti-PD-L2 agents; agents targeting other stimulatory or co-inhibitory T-cell receptors (including but not limited to CTLA-4, OX-40, and CD137); or antibody-drug conjugates (ADCs) with MMAE or MMAF payloads;
• Systemic administration of Chinese proprietary medicines with anti-tumor indications or immunomodulatory agents (including thymosin, interferon, and interleukins, except for local administration to control pleural effusion) within 2 weeks prior to the first dose;
• Active autoimmune disease requiring systemic therapy (e.g., disease-modifying antirheumatic drugs, corticosteroids, or immunosuppressants) within 2 years prior to the first dose. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement for adrenal or pituitary insufficiency) is not considered systemic therapy;
• Receipt of systemic corticosteroid therapy (excluding intranasal, inhaled, or other topical corticosteroids) or any other form of immunosuppressive therapy within 7 days prior to the first dose; \*Note: Physiologic doses of corticosteroids (prednisone ≤10 mg/day or equivalent) are permitted;\*
• History of allogeneic organ transplantation (corneal transplantation excluded) or allogeneic hematopoietic stem cell transplantation;
• Known hypersensitivity to pucotenlimab, MRG003, or any of their excipients;
• Failure to recover adequately from toxicities and/or complications of prior interventions (i.e., to Grade ≤1 or to baseline, excluding fatigue and alopecia) prior to initiation of study treatment;
• Known history of human immunodeficiency virus (HIV) infection (HIV-1/2 antibody positive);
• Untreated active hepatitis B infection (defined as HBsAg positivity with HBV-DNA copy number above the upper limit of normal of the local laboratory); \*Note: Subjects with hepatitis B may be enrolled if they meet the following criteria:\* 1) HBV viral load \<1,000 copies/mL (200 IU/mL) prior to the first dose; subjects must receive prophylactic anti-HBV therapy throughout the study treatment period to prevent viral reactivation; 2) Subjects with anti-HBc (+), HBsAg (-), anti-HBs (-), and undetectable HBV viral load are not required to receive prophylactic anti-HBV therapy but require close monitoring for viral reactivation;
• Active hepatitis C infection (HCV antibody positive with HCV-RNA level above the lower limit of quantification);
• Receipt of a live vaccine within 30 days prior to Cycle 1 Day 1; \*Note: Inactivated injectable influenza vaccines for seasonal influenza are permitted within 30 days prior to the first dose; intranasal live-attenuated influenza vaccines are not permitted;\*
• Pregnancy or breastfeeding;
• Presence of any serious or uncontrolled systemic condition, including but not limited to:
  • 1\) Resting ECG demonstrating significant, symptomatic, and poorly controlled abnormalities in rhythm, conduction, or morphology, including complete left bundle branch block, second-degree or higher atrioventricular block, ventricular arrhythmias, or atrial fibrillation; 2) Unstable angina pectoris, congestive heart failure, or chronic heart failure of New York Heart Association (NYHA) Class ≥2; 3) Any arterial thrombosis, embolism, or ischemic event (e.g., myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack) within 6 months prior to enrollment; 4) Inadequately controlled hypertension (systolic blood pressure \>140 mmHg or diastolic blood pressure \>90 mmHg); 5) History of non-infectious pneumonitis requiring corticosteroid therapy within 1 year prior to the first dose, or currently clinically active interstitial lung disease; 6) Active pulmonary tuberculosis; 7) Active or uncontrolled infection requiring systemic antimicrobial therapy; 8) Clinically active diverticulitis, intra-abdominal abscess, or gastrointestinal obstruction; 9) Hepatic conditions including cirrhosis, decompensated liver disease, or acute or chronic active hepatitis; 10) Poorly controlled diabetes mellitus (fasting blood glucose \>10 mmol/L); 11) Urinalysis demonstrating urine protein ≥2+ with confirmed 24-hour urine protein \>1.0 g; 12) Psychiatric disorder that would preclude compliance with study requirements;
  • 17\. Any medical condition, laboratory abnormality, or concurrent therapy that, in the Investigator's opinion, may interfere with study assessments, compromise subject safety, or render the subject unsuitable for study participation.